Blood coagulation is the key process involved in both haemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).
Coagulation is the result of a complex series of enzymatic reactions.
Disseminated intravascular coagulation (DIC) is a systemic secondary thrombo-haemorrhage disorder seen in consequence of primary problems, such as infections, trauma, obstetric complications, cancer and snake bites.
The most serious clinical form of DIC is characterised by excessive consumption of coagulation proteins, deposition of fibrin and bleeding. In its least serious forms, endogenous markers of thrombin generation are produced with little or no obvious coagulation problems.
Trauma patients are at increased risk of DIC. Head trauma is a particularly common cause in children.
Sepsis may occur in about 40% of trauma patients and is an important primary cause of DIC in all patients. The clinical condition is worsened by secondary fibrinolysis, which results in the formation of, for example, fibrinogen and fibrin degradation, which interfere with normal fibrin formation and platelet function.
Fibrin deposition in DIC may lead to further organ dysfunction. DIC is a major cause of acute renal failure and it also contributes to multiple system organ failure (MOF) and death. Despite improvements in the critical care and use of broad-spectrum anti-microbial agents, the mortality rate in DIC patients with severe sepsis still is high (Eisele et al, Sem. Thromb. Hemost., (1998) 24, 71).
DIC is characterised primarily by activation of procoagulants, resulting in excessive thrombin generation, hypercoagulability with intravascular fibrin formation, and platelet aggregation in the tissues, leading to thrombocytopenia (low platelet count). Further, the natural coagulation inhibitory mechanisms that neutralize thrombin fail to operate properly.
Current DIC treatments are highly individualised and are focused on treating the primary underlying disease. Without control, DIC continues despite forms of therapy directed at correcting the bleeding or thrombotic problem.
For patients with significant bleeding, to maintain haemostatic balance, replacement therapy using fresh frozen plasma (FFP), cryoprecipitate, and/or platelet concentrates is frequently used until the primary problem may be brought under control.
Endogenous anticoagulation and/or other anticoagulant treatments may be beneficial in treating DIC. Heparin has been used in patients with DIC with varying results. However, response to heparin appears to be dependent on the plasma concentration of antithrombin III (ATIII) which is usually decreased during DIC especially in patients with sepsis (Riewald and Reiss, Sem. Thromb. Hemost., (1998) 24, 53). Indeed, the use of heparin in the treatment of DIC is highly controversial, and is not generally indicated in patients with the underlying problem of trauma.
Substitution with ATIII has been found to reduce mortality in endotoxin animal models, and also in critically ill patients with sepsis (Diaz-Cremades et al, Intensive Care Med., (1994) 20, 577; Eisele et al, Sem. Thromb. Hemost., (1998) 24, 71). Larger randomised clinical trials are currently ongoing with a view to testing this hypothesis.
International patent application WO 94/29336 discloses a group of thrombin-inhibiting compounds, including HOOC—CH2—(R)Cgl-Aze-Pab-H (in which Cgl represents cyclohexylglycine, Aze represents S-azetidine-2-carboxylic acid and Pab-H represents 4-aminomethylamidinobenzene), which is also known as melagatran (see Example 1 of WO 94/29336). International Patent Application WO 97/23499 discloses prodrugs of inter alia melagatran.
Eriksson et al (Thromb. Hemost., (1998) 80, 1022 and Acta Anaesthesiol. Scand., (2000) 44, 24) and Basu et al (Exp. Opin. Invest. Drugs, (2000) 9, 1129) have evaluated the effects of melagatran during experimental endotoxaemia. The latter group postulated that melagatran may be of potential use in the treatment of septic shock.
Nonetheless, neither melagatran, nor any other individual anticoagulant, has been found to be capable of providing full restitution in experimental endotoxaemia. Thus, there remains a need for alternative and/or more effective treatments of DIC.
Dexamethasone is a well-known synthetic corticosteroid that exhibits antiinflammatory activity. It may be administered in a variety of physical forms for use in the treatment of various inflammatory conditions (see, for example, Martindale—The Complete Drug Reference, (32nd Edition), K. Parfitt (ed.), Pharmaceutical Press, London (1999), at pages 1037 to 1039).
Although international patent application WO 00/41716 discloses the general use of melagatran in the treatment of inflammatory disorders, and combinations of melagatran, derivatives and prodrugs thereof with other therapeutic agents that are useful in the treatment of inflammation are mentioned in general terms, a specific combination comprising melagatran and dexamethasone is neither mentioned nor suggested.
We have now found, surprisingly, that administration of such a combination gives rise to a notable synergistic effect in experimental endotoxaemia in rats. Such a combination is thus expected to be useful in the treatment of inter alia DIC in mammalian patients.